title: Genome-Wide Association Study of Genetic Variants in LPS-Stimulated IL-6, IL-8, IL-10, IL-1ra and TNF-α Cytokine Response in a Danish Cohort.
abstract: Cytokine response plays a vital role in various human lipopolysaccharide (LPS) infectious and inflammatory diseases. This study aimed to find genetic variants that might affect the levels of LPS-induced interleukin (IL)-6, IL-8, IL-10, IL-1ra and tumor necrosis factor (TNF)-α cytokine production.
  
  
  
  We performed an initial genome-wide association study using Affymetrix Human Mapping 500 K GeneChip® to screen 130 healthy individuals of Danish descent. The levels of IL-6, IL-8, IL-10, IL-1ra and TNF-α in 24-hour LPS-stimulated whole blood samples were compared within different genotypes. The 152 most significant SNPs were replicated using Illumina Golden Gate® GeneChip in an independent cohort of 186 Danish individuals. Next, 9 of the most statistical significant SNPs were replicated using PCR-based genotyping in an independent cohort of 400 Danish individuals. All results were analyzed in a combined study among the 716 Danish individuals.
  
  
  
  Only one marker of the 500 K Gene Chip in the discovery study showed a significant association with LPS-induced IL-1ra cytokine levels after Bonferroni correction (P<10(-7)). However, this SNP was not associated with the IL-1ra cytokine levels in the replication dataset. No SNPs reached genome-wide significance for the five cytokine levels in the combined analysis of all three stages.
  
  
  
  The associations between the genetic variants and the LPS-induced IL-6, IL-8, IL-10, IL-1ra and TNF-α cytokine levels were not significant in the meta-analysis. This present study does not support a strong genetic effect of LPS-stimulated cytokine production; however, the potential for type II errors should be considered.
authors.affiliation: Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Margit Hørup
authors.initials: MH
authors.lastname: Larsen
authors.forename: Anders
authors.initials: A
authors.lastname: Albrechtsen
authors.forename: Lise Wegner
authors.initials: LW
authors.lastname: Thørner
authors.forename: Thomas
authors.initials: T
authors.lastname: Werge
authors.forename: Thomas
authors.initials: T
authors.lastname: Hansen
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gether
authors.forename: Eva
authors.initials: E
authors.lastname: Haastrup
authors.forename: Henrik
authors.initials: H
authors.lastname: Ullum
mesh_terms: D015331:Cohort Studies; D003718:Denmark; D055106:Genome-Wide Association Study; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
chemical_list: D007378:Interleukins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha